Penicillin salts of nu-methyl-(2-hydroxy-1, 2-diphenylethyl)-amine



' ethyl) amine.

Patented July 14, 1953 PENICILLIN SALTS OF N-METHYL- 2-HY-DROXY-L2-DIPHENYLETHYL) -AMINEv Vernon V. Young, Terre Haute, Ind.,assignor to a Commercial Solvents Corporation, Terre Haute, -Ind., acorporation of Maryland No Drawing. Application January 22, 1952,

Serial No. 267,695

7Claims. (01260-2391) in order for the therapeutic activity of the saltto be retained, it must be refrigerated during storage or else rapiddeterioration of the thera-,

peutic activity occurs. Some penicillin salts are too toxic for usetherapeutically and hence must be ruled out-completely.

In addition to the stability and toxicity characteristics of penicillinsalts, consideration must also be given to their solubility properties.The expression of favorable solubility properties is foundinthemeasurement of blood levelsof penicillin at intervals after injectioninto or ingestion by the body. The longer penicillin can be found in theblood after it has been placed in the body, the more effective it isagainst the pathogenic organisms present in the body, provided they arepenicillin susceptible. If, however, blood levels of penicillin are onlymaintained for short periods after injection or ingestion of thepenicillin salt, the penicillin content of the salt is largely wastedand there-islittle or no alleviation of the pathological condition beingtreated unless there are repeated administrations of the pen icillinsalt at short intervals.

Furthermore, it has been found that about 10 .per cent ofv allpatientstreated with most previously known penicillin compounds are allergic to.the. drug and upon administrationthereof serious complications'intheform of hives often occur. Treatment is, therefore-denied a great"many people because of their allergy.

An object of the present invention is to provide stable penicillin saltcompositions of low toxicity which give prolonged blood levels ofpenicillin whether given orally or by injection, and which a morepeople. My new compositions are penicillin hydroxy -'l',2 diphenyl} vsalts of N-meth'yl- (2 N methyl (2-hydroxy-1,2-diphenylethyllaminecontains two asymmetric 'carbonatoms and thus two racemic modificationsand four optically active isomers arepossible. Thepenicillinsalt-of thelevo isomer of the erythro pair of N -methyl(2-hydroxy-1,2-diphenylethyl) amine can be prepared by mixingone-equivalent of a water soluble penicillin salt such as potassiumpenicillin G in aqueous-solution with two equivalents of an aqueoussolution of thehydrochloride of dl-N-methyl-(2-hydroxy-l,2-diphenylethyl) amine obtained by the reductive .aminationof benzoin with monomethylamine. Thecrystalline penicillin salt of l Nmethyl (2-hydroxy-LZ-Giphenylethyl)- amine-precipitates from the aqueoussolution and is recovered therefrom by filtration and dried. (Nitrogenanalysis: calculated 7.48% found 7.38%. Carbon analysis: calculated66.28%; found 66.33%. Hydrogen analysis: calculated 6.28%;.-found 6.18Melting point 186-191" C. with decomposition. Specific rotation in 50%acetone-water at 2.5? C ,taken within one-half hour after dilution is+124i5.) The dextro isomer of the same pair does not form asalt withpenicillin under the above-conditions but the unreacted isomer can berecovered from the filtrate by adjusting the pH between 9-10 with anaqueous solution of sodium hy'droxide. One mole of potassium penicillinis reacted with two moles of dl N methyl 2 hydroxy-LZ-diphenylethyl)amine in order-to obtain near quantitative yields of thesaltof thelevoisomer based on the quantity. of penicillin useddue to the presence ofthe dextro isomer.

The penicillin salt of' the dextro isomer can be prepared by reacting itwith an equivalent amount of. free benzyl-penicillinic acid in anorganic solvent such as ethyl ether or butyl acetate. Crystallziationcan be induced by seeding or scratching. (Nitrogen analysis: calculated7A8 found 7.33 Carbon analysis: calculated 66.28%; found 66.21%.Hydrogen analysis: calculated. 6.28% found 6.18%. Melting point 148-151". C. with'idecomposition. Specific rota- .tion in.50% acetone-waterat 25 C. taken within one-half hourafter' dilution is +220 i5.) Theterms dextro and'levo or d andl as used in'this specification and theattached'claims refer to the dextro and levo isomers-"6f the erythropair of N- 'methyl (2 hydroxy-l,2diphenylethyl)amine.

-themethod of Welsh. (Journal. American Chem- 3 ical Society, vol. 69,page 128; Journal American Chemical Society, vol. 71, page 3500) asapplied to ephedrine, which consists essentially of a'cetylating thedeX-tro and levo isomers of the erythro pair and hydrolyzing theacetylated product with dilute acid in order to bring about inversion.The penicillin G salts of the levo and dextro isomers forming the threoracemate of N-methyl-(Z-hydroxy-l,Z-diphenylethyl) amine are prepared byreacting an isomer of the base with free penicillin G in ethyl ethersolution. The precipitated amorphous salts are isolated by decanting theether and then drying. The dextro and levo isomers of the three racemateof N-methyl-(2- hydroxy-1,2-diphenylethyl) amine in this specificationare denominated d and 1' respectively. The penicillin G salt of the disomer has a specific rotation of +192i5 in acetone at 25 C. takenwithin one-half hour after dilution while the specific'rotation of thepenicillin G salt of the 1' isomer taken under the same conditions is+155i5. 17he l and d isomers can be employed to form salts of otherforms of penicillin just as described above for penicillin G,

Blood level tests were conducted wherein my new penicillin salts ofN-methyl-(2-hydroXy-1, 2-diphenylethyl) amine were given orally. andin.- jected intramuscularly into dogs, the amount of penicillin in theblood stream being measured at definite intervals after administration.The following table shows the blood levels obtained after a portion ofmy new penicillin G salt of l N methyl (Z-hydroxy-1,2-diphenylethyl)amine containing the indicated number of units of penicillin wasinjected intramuscularly as an aqueous suspension.

TABLE I [Blood level; 120 mesh aqueous suspensionintramuscularly; unitspenicillin/ml. blood] Hours Dog No. 6 12 24 36 48 60 72 TABLE. II

. 0 [Blood levels; units penicillin/ml. blood; procaine penici1lin12mesh aqueous suspension-intra.muscularly.]

Hours Dog No. gg

TABLE III [Blood levels; 100,000 unit tabletoral1y; units penicillin/ml.blood.]

Hours Dog No.

The following table shows blood levels obtained when my new penicillin Gsalt of d-N- methyl- (2-hydroxy-1,2-diphenylethyl) amine wasadministered orally, 100,000 units of penicillin being administered toeach dog.

TABLE IV [Blood levels; 100,000 unit tabletorally; units penicillin/ml.blood] Hours Dog No.

The following table indicates blood levels obtained when my newpenicillin G salt of l-N- methyl- (2-hydroxy-1,2-diphenylethyl) aminewas injected intra'muscularly into dogs as a suspension in peanut oil.

TABLE V [Blood levels; 60,000 units; oil suspension-intramusc ularly;units penicillin/ml. blood] 7 Hours Dog No. i

TABLE VI [Blood levels; procaine penicillinoilsuspension-intramusculerly; 60,000 units per dog; units penicillin/ml.blood] 1 Hours Dog No.

The following table isa*summary of clinical data obtained when my newpenicillin G aner l-N-methyl- (2' hydroxy 1,2 diplienylethyltamine wasused. therapeutically in'man. ideaeh oase a single 300,000 unit doseofjmy riew dmpound was injected intramuscularly "aind tlieblood levelobtained in the usual manner.

TABLE VII [Blood levels; 300,000 units; aqueous'suspe'nsionintramuscularly in man; units penicillin/ml. blood] HoursPatient 0. 125 0. 125 0.06 0. 25 0. 125 0. 03 0. 06 0. 125 0. 06 0.03 0.03 0. 25 O. 125 0.03 0. 06 O. 25 0. 06 0 0 0. 06 0. 125 0.06 0 0. 125 00 0 O. 25 O. 125 0 0 0. 5 0. 125 0 0 0. 5 0.03 0.03 0 0 0.03 0 0 0. 25O. 125 0. 06 0.03 0. 125 0. 06 0. 03 0.03 0. 125 0. 125 0 0 0.06 0. 06 00 0. 25 0. 06 0.06 0 0. 25 0. 125 0. 06 0. 03 0. 25 0. 125 0.06 0.06

The following table is also offered for comparison. purposes. It showsblood levels obtained when procaine penicillin G was injectedintramuscularly into man, 300,000 units of penicillin being administeredto each patient.

TABLE VIII [Blood levels; 300,000 units of procaine penicillin G aqueoussuspension intramuscularly in man; units penicillin/ml. blood] HoursPatient It can be seen from a comparison of Tables VII and VIII that mynew penicillin G salt of N methyl-(Z-hydroxy-1,2-diphenylethy1) aminegives consistently longer blood levels in man when injectedintramuscularly than the form of the antibiotic currently consideredmost efiicient.

In another series of tests twenty-three selected patients were treatedwith both procaine penicillin G and the penicillin G salt ofl-N-methyl-(2- hydroxy 1,2 diphenylethyl) amine. Of the twenty-threepatients treated, twelve were hyper-- sensitive to procaine penicillinG, while but one was sensitive to the penicillin G salt of l-N-methyl-(z-hydroxy 1,2 diphenylethyl) amine, this patient developing anurticarial eruption. A further advantage in the use of my new penicillinsalts is illustrated in the following case. Twenty-four hours afterstarting regular crystalline procaine penicillin G therapy for a pelvic6 infection; thepatientdeveloped a severe urticarial rash and edemaaccompanied by slight elevation of temperature. The penicillin G s'altofl-N- methyl- (z-hydroxy-1;2 dipheny1ethyl) amine was immediatelysubstituted' and all'signs of reaction cleared completely in 36 hoursand did not return duringthe entire'course of treatment with my newpenicillin salt. Thus it is shown to be possible to give mynewpenicillinsalt even in the face of known periicillin sensitivity.

The following table shows the results of toxicity tests of the newpenicillin G salt of l-N-methyl- (2 hydroxy-1,2-diphenylethyl) amineconducted on laboratory mice. The table shows the amount of my newcompound which can be administered without any mouse fatalities and theamount given to produce a 50% kill or the mice tested. The penicillinsalt was injected intraperitoneally and subcutaneously as indicated inthe table.

The minimal dose of the pencilillin G salt of l Nmethyl-(Z-hydroxy-1,2-diphenylethyl)- amine showing cutaneous irritationis greater than 2100 mg. per kg. of body weight of the test mice butless than 400 mg. per kg. of body weight of the test mice. A single doseof 5,000,000 units of the penicillin G salt ofl-N-methyl-(Z-hydroxy-l,2-diphenylethyl) amine in aqueous suspension wasinjected subcutaneously into two dogs and the dogs subsequently observedfor a period of 48 hours. No toxic or irritative symptoms Were observedduring the 48 hours.

The following table shows the results of acute toxicity tests of the newpenicillin G salt of d- N methyl-(2-hydroxy-1,2-diphenylethyl) amineconducted on laboratory mice. The salt was given orally and injectedintraperitoneally and subcutaneously as shown in the table.

TABLE X Mouse toxicity LDo D50 rug/kg. of Body Weight of Test Mice Froma consideration of the above tables it can be seen that my new compoundsare distinct improvements over procaine penicillin G which has beenconsidered to be the best form of penicillin available to the trade.

My new compounds are therapeutically effective antibiotic compounds andare useful in treating diseases in man and animals caused by penicillinsusceptible organisms.

7 1 Now having disclosed my invention what I 5; The penicillin G salt ofdN-methyl-(2-hyclaim is: droxy-1,2.-diphenylethyl)amine.

1- The pe cill Sa Of N- t y -(iz-hy- 6. The penicillinGsalt ofd1(threo)-N-methyl- Y-L iphenylethy1) amine.(2-hydroxy-1,2-diphenylethyl) amine.

The penicillin G Salts of -melJhyI-(Z-hy- 5 7. The penicillinG salt ofl-(threo)-N-methyldroxy-1,2-diphenylethyl) amine.(Q-hydroxy-1,2-dipheny1ethyl) amine.

3. The penicillin G salt of dl-N-methyl-(Z- hydroxy-LZ-diphenylethyl)amine.

4. The penicillin G salt of 1-N-methyl-(2-hydroxy-1,2-diphenylethyl)amine. 10

VERNON V. YOUNG.

No references cited.

1. THE PENICILLIN SALTS OF N-METHYL-(2-HYDROXY-1,2-DIPHENYLETHYL)AMINE.